This project aims to provide proof-of-principle for the novel concept that the natural protein C pathway couples and coordinates the function of the hematopoietic system to the activation state of the blood coagulation system. We propose that the key components of the natural protein C anticoagulant and cytoprotective pathway, i.e. the endothelial protein C receptor (EPCR), the modulator of thrombin function thrombomodulin (Thbd), and the key effector protease of the protein C pathway, activated protein C (aPC), regulate in a physiologically relevant manner the function of hematopoietic stem and progenitor cells (HSPC). Expression of EPCR and Thbd on HSPC enables the hematopoietic system to sense and respond to the presence of the coagulation proteases thrombin and aPC generated in the HSPC micro-environment. As coagulation system activation is an intrinsic part of the response to injury, the protein C system adapts hematopoiesis to the specific challenges posed by inflammatory stress or similar pathological conditions. AIM 1 is based on the novel observation that the protein C system protects HSPC against otherwise lethal radiation exposure, and investigates the mechanistic details mediating this protection against injury. AIM 2 answers the question whether systemic alterations of coagulation system activity, as they may occur during inflammation, cancer, cardiovascular events, and many other disease, change the quality or quantity of the hematopoietic output; and whether this interaction between coagulation and hematopoiesis is again mediated through the activity of the protein C system. AIM 3 investigates how the protein C pathway regulates the response of the hematopoietic system to chemokine- or inflammation-induced HSPC mobilization. Pilot studies suggest that the protein C pathway may have profound effects on the efficacy of clinically employed mobilization protocols for stem cells, and may provide signals to hematopoietic stem cells that trigger the rapid production of regulatory immune cells. To test these hypotheses we utilize genetically engineered mice lacking the key receptors EPCR and Thbd, and conduct in vivo tests that reveal how disruption of the protein C pathway, or pharmacologic manipulation thereof by infusion of aPC, affects hematopoiesis. Beyond documenting a novel physiologic connection between blood coagulation and hematopoiesis, outcomes of the study lay the groundwork for the rationale design of therapeutic applications and interventions targeting this cross-talk. These discoveries have the potential to significantly impact the current understanding of hematopoiesis and approaches to its pharmacologic manipulation. RELEVANCE (See instructions): The study investigates a novel interaction between the blood coagulation mechanism and the function of the hematopoietic system, that is mediated by the natural protein C pathway, and points to novel approaches towards improving transfusion protocols, emerging cellular therapies, and immune functions of hematopoietic stem cells.